1. Field of the Invention
This invention relates to methods and devices for assessing and modifying the circadian cycle in humans. More specifically, the invention relates to methods and devices for using scheduled exposure to bright light, and advantageously also periods of darkness, to alter the circadian cycle of humans to a desired phase and amplitude.
2. Related Art
It is known in the art that humans exhibit circadian (daily) cycles in a variety of physiologic, cognitive, and behavioral functions. The cycles are drives by an internal biological clock or circadian pacemaker which has been located in the brain and are not just passive responses to periodic environmental changes. It is known that humans exhibit different degrees of alertness, performance, and proneness to accidents at different phases in their circadian cycle.
Often, the activities in which humans wish to engage do not coincide in time with the most appropriate point in the circadian cycle. For instance, transmeridian travelers experience what is commonly referred to as "jet lag." This phenomenon occurs when the internal, physiological circadian phase of the traveler has not yet adapted to the geophysical time of his destination. Individuals who travel from west to east often experience sleeplessness late in the evening at their destination, with a corresponding difficulty in awakening on time in the morning. Similarly, those who travel from east to west often experience a tendency to sleep earlier in the evening and arise earlier in the morning than is appropriate for the locale of their destination. The travelers' internal, physiological cycle lags (or leads) their desired activity-rest cycle. Symptoms are worse and last longer when travelers must cross more than three or four time zones, especially when traveling west to east. West to east travel is more difficult than east to west travel because the intrinsic period of the human circadian pacemaker is greater than 24 hours (averaging about 24.3 to 25.0 hours in normal young men). Therefore, in the absence of an environmental synchronizing cue, the phase position of the pacemaker tends to drift to a later hour (i.e., in a manner equivalent to westward travel at a rate of about one time zone per 1 to 2 days). The insomnia associated with jet lag may be postponed two or three days if the travelers are sleep-deprived as a result of the journey, since sleep deprivation makes it easier to sleep at an adverse circadian phase. However, the essential circadian nature of jet lag is demonstrated by nocturnal insomnia and excessive daytime sleepiness which typically occur within two to three days of arrival.
In a similar fashion, people who work in professions requiring them to work at night, such as factory workers, medical personnel, police, and public utilities personnel, experience a desynchrony between the activities in which they desire to engage and their physiological ability to engage in such activities. Such "shift workers" often experience an inability to sleep soundly during their non-working hours. This misalignment between internal circadian phase and scheduled work hours at night also manifests as increased drowsiness during the early morning hours of 3:00-7:00 a.m., assuming a habitual waketime of 7:00 to 8:00 a.m. (These times would be modified if the habitual waketime were at a different hour.) It is during this time frame that most people's circadian cycles are at their troughs, implying that they experience minimum alertness and maximum proneness to accident or error. These workers then experience corresponding difficulty sleeping during the daytime hours after they have worked at night, again because of circadian phase misalignment. This results in sleep deprivation, which exacerbates the problem they experience with alertness and performance on their subsequent night shifts. For workers in the medical field or for those individuals who monitor the processes in nuclear power plants, for example, such decreased alertness can have (and already may have had) disastrous consequences.
Three different approaches have been used previously to reduce the deleterious effects of shift work schedules on the performance of shift workers and the safety of shift work operations. One, used primarily in Europe, is to very rapidly rotate shift workers such that they never work more than 1-2 night shifts in a row and do not attempt to adapt to night shift work. The second approach is to select shift workers on the basis of the amplitude of the temperature cycle for shift work, since it has been reported that individuals with certain characteristics of temperature cycle amplitude can adapt more easily to rotating shift work schedules (see A. Reinberg et al., "Circadian Rhythm Amplitude and Individual Ability to Adjust to Shift Work." Ergonomics, Vol. 21 (1978), pp. 763-766). The third approach has been to apply circadian principles in the design of work schedules (see C. A. Czeisler et al., "Rotating Shift Work Schedules That Disrupt Sleep Are Improved by Applying Circadian Principles." Science, Vol. 210 (1980), pp. 1264-1276).
There are various categories of sleep-related and affective disorders which are through to be related to misalignment between the internal circadian cycle and the external activity-rest cycle. For example, the elderly often experience a phase advance of the internal circadian pacemaker to an earlier hour, which manifests as a tendency to be fatigued and tired earlier in the evening, and to spontaneously awake earlier in the morning, than was the case earlier in their lives. Many elderly subjects also have a reduced amplitude of the endogenous component of the body temperature cycle, suggesting that the output of the circadian pacemaker may be attenuated with age. This may contribute to the increased tendency for both daytime napping and nocturnal arousals reported in the elderly.
Other sleep scheduling disorders not totally determined by age, such as delayed-sleep-phase insomnia, are also known. Finally, the misalignment between the internal circadian cycle and the external activity-rest cycle may contribute to certain affective disorders, including depression.
Various techniques have been attempted in the past to correct the above-noted abnormalities in phase or amplitude of the circadian system. In the case of activity-induced phase misalignment or desynchronization, as in the case of transmeridian travelers and shift workers, the goal of the methods was to facilitate the speedy adjustment to the "destination" place or time. In the case of non-activity-induced phase misalignment, such as age-related circadian phase advance and delayed sleep phase insomnia, the goal of the methods was to provide prompt and stable adjustment of the circadian phase to match the desired activity-rest (sleep-wake) cycle. These various alleged phase-shifting techniques involved special diets, drugs, exercise, or direct manipulation of the sleep-wake cycle. For various reasons, such as the presence of side effects, impracticality of implementation and/or simple ineffectiveness, such techniques have not found practical utility. No techniques to date have allowed rapid and efficient circadian phase-shifting.
Other researchers have employed the application of light to phase-shift the circadian cycle of humans. At first, it had been thought that humans were the exception in the animal kingdom to the rule that light provided a means by which the internal circadian phase was directly synchronized to the external periodic environmental cycle. Although later research showed that human circadian cycles appeared to respond to timed application of light, the researchers who attempted to determine the effects of light on human circadian cycles were confounded by the lack of an accurate means of assessing the circadian phase and amplitude resetting capacity of a given human subject. Without being able to rapidly assess the phase and amplitude of an experimental subject before and after a series of applications of light, researchers were unable to accurately determine the effect of those applications of light.
It is therefore desirable to design a reliable and accurate method of assessing the effect of a particular stimulus on human circadian phase and amplitude in a reasonably short period of time. Such an accurate and efficient circadian phase and amplitude assessment method would allow accurate measurement of the effects of different exposures to light on phase and amplitude modification.
An early method of assessing the phase-shifting effect of a particular stimulus on the circadian phase of lower animals was embodied in procedures carried out to derive a hypothetical construct called a Phase Response Curve (PRC), developed in early experiments conducted by Hastings and Sweeney, DeCoursey et al., and Pittendrigh et al. See Czeisler et al., "Chronotherapy: Resetting the Circadian Clocks of Patients with Delayed Sleep Phase Insomnia," Sleep, Vol. 4, No. 1 (1981), pp. 1-21. See also Lewy et al., "The Use of Bright Light in the Treatment of Chronobiologic Sleep and Mood Disorders: The Phase Response Curve," Psychopharmacology Bulletin, Vol. 19, No. 3 (1983), pp. 523-25. The PRC was based on early research on nocturnal animals which spent most, if not virtually all, of the duration of the experiment in total darkness. When in total darkness, the circadian activity rhythms of these animals "free-run" since they lack any means by which they may be "reset" to the 24-hour geophysical day. The results of such experiments are therefore of limited usefulness in determining the effect of a more complex lighting schedule which includes exposure to bright light, ordinary indoor light, and darkness, in causing phase shifts and amplitude changes in the internal physiological circadian cycle of humans. Also, the human rest-activity cycle is not an accurate marker of endogenous circadian phase and humans cannot practically be expected to spend weeks in total darkness punctuated by occasional episodes of bright light.
It was known that the core body temperature of humans varied with the circadian cycle. By observing subjects who were placed in isolation from any external time cues (or "zeitgebers") for a time period on the order of 30 days, researchers could monitor the core body temperature to discern a long-term trend to the troughs of the body temperature cycle. The long-term trend of body temperature troughs was used to determine (using, for example, Fourier analysis) the period of the "free-running" cycle of the individual subject. Furthermore, about one quarter of the subjects studied in these longterm studies exhibited an activity-rest cycle which was desynchronized from the period of the body temperature cycle (spontaneous internal desynchronization), thereby revealing the intrinsic period of the endogenous circadian pacemaker which drives the endogenous component of the body temperature cycle. This technique of period and phase determination will hereinafter be referred to as the desynchronized wave form eduction technique. (See S. H. Strogatz, The Mathematical Structure of the Human Sleep-Wake Cycle, Lectural Notes in Biomathematics No. 69, Heidelberg, FRG: Springer-Verlag, 1986). Although this method's validity was enhanced by the later-demonstrated stability of the period of the internal circadian cycle, the 1-2 month length and cost of this assessment technique rendered it impractical for all clinical applications and even many laboratory experiments. Unfortunately, such lengthy and costly experiments were once necessary to eliminate the confounding effects of activity on the body temperature cycle. However, for statistical reasons, the inaccuracies of the phase determinations incorporated in this 1-2 month desynchronized waveform eduction technique for period and phase assessment are the greatest at the beginning and the end of the study. The desynchronized waveform eduction technique is therefore neither practical nor useful for determining the phase-shifting effect of a particular stimulus delivered between two such (30-60 day) phase assessment procedures.
Lewy et al. later attempted to use melatonin as an indicator of circadian phase, based on the observation that light above a certain brightness threshold (2500 lux) suppresses the secretion of melatonin. See Lewy et al., "Immediate and Delayed Effects of Bright Light on Human Melatonin Production: Shifting `Dawn` and `Dusk` Shifts the Dim Light Melatonin Onset," Annals New York Academy of Sciences, 1985, pp. 253-59. However, no reliable correlation has yet been shown between melatonin secretion levels and the phase or amplitude of the endogenous circadian cycle using generally accepted techniques such as the desynchronized waveform eduction technique. Furthermore, the shifts reported by that method were modest, and required an impractically large number of treatments. Daily exposure to light treatments for one week were typically required to achieve a 1- or 2-hour phase shift. (See A. J. Lewy et al., "Antidepressant and Circadian Phase-Shifting Effects of Light", Science, Vol. 235, pp. 352-54 (1987). See also Honma, K., Honma, S., Wada, T., "Phase Dependent Responses of Human Circadian Rhythms to a Bright Pulse: Experiments in a Temporal Isolation Unit", J. Physol. Soc. Jap., Vol. 48, p. 416 (1986).)